We present here research proposals designed to creatively conceptualize, produce and evaluate vaccines to protect against AIDS. The theme of our National Cooperative Vaccine Development Group is "Immunological and Biological Strategies for an AIDS Vaccine." We intend to thoroughly assess the precise targets of antibodies and T lymphoctyes among SIV1 and HIV1 proteins, to elucidate molecular mechanisms that regulate the expression of SIV1 and HIV1 genes, to use the immunological and biological information to construct the best SIV subunit vaccines using recombinant DNA techniques, to test the immunoprophylactive efficiency of the SIV subunit vaccines in primates and finally, if an SIV vaccine works, to fashion a similar HIV1 subunit vaccine for human AIDS. The Principal Investigator, Dr. Richard Young (Whitehead Institute), will use newly developed recombinant DNA technology to efficiently survey all possible SIV and HIV polypeptides to determine the precise targets of the antibody and helper T lymphocyte (CD4) response during infection. His program will also involve the development of a novel vehicle from M. bovis BCG that can be constructed to produce and deliver HIV protein antigens for immunoprophylaxis. The recombinant DNA tools and products will be provided to Dr. Robert Schooley (Massachusetts General Hospital) to investigate what protein antigens are targets of the cytotoxic T cell (CD8) response during infection. Dr. Herman Eisen (MIT) will collaborate with Drs. Young and Schooley to help define the cellular targets of killing and the mechanisms involved in killing. Dr. David Baltimore (Whitehead Institute) will investigate molecular mechanisms by which viral replication could be attenuated in the cell and will provide information about the regulation of SIV and HIV gene expression. Based on this immunological and molecular biological information, subunit vaccine candidates will be formulates for simian AIDS by the group as a whole and such candidates will be constructed and produced by Dr. Rosenburg (Smith Kline). Dr. Ronald Desrosiers (New England Regional Primate Research Center) will investigate SIV neutralization by antibodies and will test the vaccine candidates produced by Smith Kline in primates for protective efficacy. The immune response to vaccination and subsequent challenge by live virus will be studied by the immunological programs (Young and Schooley, in collaboration with Eisen). The entire group will use information derived from the primate experiments to formulate and produce a vaccine for human AIDS.